Process for preparing (±)-2,3-dihydro-1H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates

ABSTRACT

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate intermediates of the formula, ##STR1## in which each R is independently H or lower alkyl, 
     are prepared from di(lower alkyl) 1,3-acetonedicarboxylates.

CROSS-REFERENCE TO RELATED APPLICATION

This applicatio is related to the subject matter of our copending andcommonly assigned U.S. patent application Ser. No. 07/003,162, filedJan. 14, 1987, for "Process for Preparing(±)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates", which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to pyrrolo[1,2-a]pyrroles, and especially to thesynthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acidand its dialkyl esters.

2. Background to the Invention

5-Aroyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids, alsoknown as 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids, offormula I, and the ##STR2## pharmacologically acceptable salts andesters thereof, are useful as analgesic, anti-inflammatory, andanti-pyretic agents for mammals, including man. They are also smoothmuscle relaxants. Two exemplary compounds under clinical study in manare ketorolac,5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, (I,Ar=C₆ H₅), and anirolac,5-p-anisoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, (I,Ar=p--CH₃ O--C₆ H₅), both disclosed in U.S. Pat. No. 4,089,969 toMuchowski et al. Other compounds, where the 5-aroyl substituents aresubstituted or unsubstituted benzoyl, furoyl, thenoyl, and pyrroyl, andwhere the 6-position on the pyrrolo-pyrrole nucleus is optionallysubstituted by lower alkyl of halogen, and the uses thereof, are alsodisclosed in a series of patents assigned to Syntex (U.S.A.) Inc.,beginning with U.S. Pat. No. 4,089,969, and including U.S. Pat. Nos.4,087,539; 4,097,579; 4,140,698; 4,232,038; 4,344,943; 4,347,186;4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759;4,353,829; 4,397,862; 4,457,941; and 4,454,151. U.S. Pat. Nos. 4,511,724and 4,536,512, assigned to Merck & Co., Inc., disclose 5-(substitutedpyrrol-2-oyl)-2,3-dihydro-1e,uns/H/ -pyrrolo[1,2-a]pyrrole-1-carboxylicacid derivatives and5-(2,3-dihydro-1H-pyrrolo[1,2-a]pyrrol-2-oyl)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylicacid derivatives, respectively; while U.S. Pat. No. 4,533,671, alsoassigned to Merck & Co., Inc., discloses5-(2,3-dihydro-1H-pyrrolo[1,2-a]pyrrol-2-oyl)-2-pyrrolealkanoic acidsand analogs.

Various methods for the preparation of these pyrrolo-pyrroles areexemplified in the patent and chemical literature, and many proceedthrough a common intermediate,2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid, (II, R=H),or its dialkyl ester; ##STR3## the preparation of which from dimethyl1,3-acetonedicarboxylate, ethanolamine, and a haloacetaldehyde isdisclosed in, for example, U.S. Pat. No. 4,089,969, which isincorporated herein by reference. The reaction scheme set forth in thatpatent: ##STR4## includes the reaction of equimolar amounts ofethanolamine (III) and dimethyl 1,3-acetonedicarboxylate (IV) to form asolution of the hydroxyenamine (V), which is then treated, preferably insitu, in a suitable organic solvent (aprotic solvents such asacetonitrile, dichloromethane, etc. are exemplified) under anhydrousconditions, with a 2-haloacetaldehyde at elevated temperatures toproduce the N-(2-hydroxyethyl)pyrrole (VI). Compound VI is esterifiedwith methanesulfonyl chloride to produce the mesylate (VII), which isoptionally converted to the N-(2-iodoethyl)pyrrole (VIII) by reactionwith sodium iodide. Either of compounds VII and VIII may be converted todimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (II,R=CH₃) by treatment with sodium hydride in dimethylformamide. Thethus-formed dimethyl2,3-dihydro-1H-pyrrolo[1,2-a]-pyrrole-1,7-dicarboxylate may then beselectively 7-decarboxylated and 5-aroylated, by methods such as thosedescribed in the previously-cited patents and in U.S. Pat. No. 4,496,741to Doherty, to yield a5-aroyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (I). Asimilar process, involving the reaction of ethanolamine, dimethyl1,3-acetonedicarboxylate, and a halomethyl alkyl ketone, bypasses thehydroxyenamine (V) and produces the 4-alkyl analog of (VI) directly.That compound may be converted to the pyrrolo-pyrrole in the same manneras for the 4-unsubstituted compound previously described.

Processes for the preparation of 5-aroyl-N-R-pyrrole-2-acetic acid,where R is H, lower alkyl, or benzyl, and analogous compounds aredisclosed in U.S. Pat. Nos. 3,752,826; 3,865,840; and 3,952,012 toCarson. They include, for the 4-alkyl substituted but not for the4-unsubstituted compounds, the reaction between a lower alkylamine, adi(lower alkyl) 1,3-acetonedicarboxylate, and a chloromethyl lower alkylketone, "preferably in an aqueous medium", followed by pouring intoice-cold hydrochloric acid, to produce compounds of formula IX, whereeach of R, R', and R" is lower alkyl. ##STR5## A similar process for the4-unsubstituted compounds (IX, R'=H) using chloroacetaldehyde isdisclosed in U.S. Pat. No. 4,048,191 to Carson.

U.K. Published Application No. 2 034 304 A, assigned to Mallinckrodt,Inc., discloses a process for the preparation of compounds of formulaIX, wherein R' may be hydrogen or alkyl, by either (a) forming atwo-phase reaction medium of an aqueous solution of the alkylamine andan inert, water-immiscible organic solvent, and adding the dicarboxylateand ketone (or aldehyde) substantially simultaneously, or (b) adding thedicarboxylate and ketone substantially simultaneously, with the ketonein excess, to an aqueous alkylamine. Preferably, dicarboxylate andexcess ketone are added to an alkylamine dispersion.

A number of patents assigned to Ethyl Corporation, including U.S. Pat.Nos. 4,565,878; 4,565,879; 4,374,255; 4,388,468; 4,383,117; 4,455,433;and 4,333,878, disclose other modifications of the Carson syntheses.U.S. Pat. No. 4,565,878 discloses the addition of a water-immiscibleco-solvent [a halogenated hydrocarbon of good solubility for both thedi(lower alkyl) 1,3-acetonedicarboxylate and the product] to the mixtureof chloromethyl lower alkyl ketone, dicarboxylate, and aqueous loweralkylamine. U.S. Pat. No. 4,565,789 discloses the use of an aromatichydrocarbon as the co-solvent. U.S. Pat. No. 4,374,255 discloses theaddition of "a solids formation inhibiting amount of a lower alkanol" tothe ketone/dicarboxylate/aqueous alkylamine mixture. The reaction isnormally carried out in the presence of a co-solvent as in U.S. Pat.Nos. 4,565,878 or 4,565,879. U.S. Pat. No. 4,388,468 discloses atwo-stage process in which (a) the ketone is added to a pre-mixed cooledsolution of the alkylamine and the dicarboxylate in a suitable solvent(e.g. aromatic hydrocarbons, chlorinated hydrocarbons, water, ormixtures thereof) at a temperature less than 60° C., followed by (b)heating the reaction mixture to 70°-100° C. U.S. Pat. No. 4,383,117discloses the use of an anhydrous lower alkylamine instead of an aqueoussolution, and the use of a single-phase non-aqueous reaction medium.U.S. Pat. No. 4,455,433 discloses the addition of "a yield-enhancingamount of an acid having a dissociation constant of at least 1.3×10⁻⁵ at25° C." to a ketone/dicarboxylate/(preferably anhydrous) loweralkylamine mixture, preferably in an organic solvent. U.S. Pat. No.4,333,878 discloses the synthesis of compounds of formula IX by thereaction of an enamine (X) ##STR6## with a 2-carboxy-1-nitroalkane (XI,R*=lower alkyl, tolyl, or benzyl). The enamine may be prepared by thereaction of a di(lower alkyl) 1,3-acetonedicarboxylate with a loweralkylamine in "a suitable solvent, such as ethanol or methanol",followed by evaporation of the solvent and heating to dehydrate thethus-formed carbinolamine to the corresponding enamine.

Albert et al., in U.S. Pat. No. 4,363,918, disclose the synthesis ofcompounds of formula IX where R is lower alkyl, R' is hydrogen or loweralkyl, and R" is H by the reaction of 1,3-acetonedicarboxylic acid withClCH₂ COR and a lower alkylamine, preferably by the slow addition of anaqueous solution of the lower alkylamine to an aqueous solution of theacid, followed by slow addition of the 1-chloro-2-alkanone, with bothadditions preferably occurring below 20° C. or lower.

European Published Applications Nos. 92 487 and 105 664, assigned toMontedison S.p.A., disclose the preparation of compounds of formula IXwherein R is CH₃ and R" is H, and R' is CH₃ (EP92487) or H (EP105664) bythe reaction of 1,3-acetonedicarboxylic acid or an alkali metal saltthereof with methylamine and a halo(ketone or aldehyde) in aqueoussolution, preferably by adding the haloketone to an aqueous mixture ofthe methylamine and the dicarboxylic acid.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to the preparation of2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates of formula XII,##STR7## in which each R is independently H or lower alkyl,

from di(lower alkyl) 1,3-acetonedicarboxylates.

The preparation may be represented schematically: ##STR8## in which R isas previously defined;

Ms is mesyl; and

X is halogen.

In a second aspect, this invention relates to novel compounds of formulaXVI, which are useful as intermediates in the process herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

"lower alkyl", denoted generally by R (which may also denote hydrogen,though that is not "lower alkyl"), refers to straight, branched, orcyclic saturated hydrocarbon radicals having from one to six carbonatoms, e.g. methyl, ethyl, isopropyl, cyclopropylmethyl, pentyl,cyclohexyl, and the like. Preferred lower alkyls are methyl, ethyl, andn-propyl, and a particularly preferred lower alkyl is methyl. If morethan one alkyl radical is present in a given molecule, each may beindependently selected from "lower alkyl" unless otherwise stated.

"lower alkoxide", "lower alkanol", "lower alkylamine", "lower alkylester", and similar terms refer to alkoxides, alkanols, alkylamines,alkyl esters, etc. in which the (or each) alkyl radical is a "loweralkyl" as defined above.

"halogen", denoted generally by X, refers to chlorine, bromine, oriodine. Preferred halogens are chlorine and bromine.

"aprotic polar solvent" includes organic solvents which may be eitherwaste-immiscible, such as halogenated hydrocarbons, e.g. methylenechloride, chloroform, etc., or water-miscible, such as tetrahydrofuran,dimethoxyethane, bis(2-methoxyethyl) ether (diglyme), dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide, etc. The solvent may alsocontain minor proportions of aprotic non-polar solvents such ashydrocarbons, e.g. cyclohexane, toluene, and the like, provided that thesolvent properties are largely determined by the polar solvent.

"weak base" refers to the alkali metal or alkaline earth salt of a weakacid, e.g. sodium acetate, potassium bicarbonate, etc., or to a buffermixture (such as NaH₂ PO₄ /Na₂ HPO₄) giving a similar pH.

"strong base" refers to bases such as alkali metal hydroxides, loweralkoxides, hydrides, di(lower alkyl)amines, and the like, e.g. sodiumhydroxide, potassium methoxide, sodium hydride, lithiumdi(isopropyl)amine, lithium bis(trimethylsilyl)amine, etc.

"mesyl", denoted by Ms, refers particularly to methanesulfonyl, butincludes other equivalent alkyl- or arylsulfonyls, such asethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and the like.

"water-miscible co-solvent" includes lower alkanols, di(lower alkyl)ketones, tetrahydrofuran, dioxane, sulfolane, dimethylformamide, and thelike. Preferred co-solvents are methanol, acetone, and similar C₁ or C₂alkyl alcohols and ketones.

Starting Materials and Purification

Dimethyl 1,3-acetonedicarboxylate is commercially available (Aldrich),as is 1,3-acetonedicarboxylic acid, also known as 3-oxopentanedioicacid. Other di(lower alkyl) 1,3-acetonedicarboxylates may readily beprepared from either the dimethyl ester or, preferably, the diacid, byesterification techniques well-known to the art. However, there is noparticular advantage in varying the alkyl groups, so that the dimethylester is preferred.

The starting materials and the intermediates of formulae XIII, XIV, XV,and XVI may be isolated, if desired, using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula XII

In Step 1, a di(lower alkyl) 3-(2-haloethylamino)-2-pentenedioate("haloenamine") is prepared from a di(lower alkyl)1,3-acetonedicarboxylate, either by direct reaction with a2-haloethylamine hydrohalide salt, or by reaction with2-hydroxyethylamine (2-aminoethanol) followed by replacement of thehydroxy group by a halide.

In Alternate I (which is preferred), the di(lower alkyl)1,3-acetonedicarboxylate is treated with a 2-haloethylamine hydrohalidesalt in aqueous solution. The solution preferably has a pH between 5 and12, more preferably between 5 and 8. Typically, the pH is controlled byemploying an aqueous solution of a weak base, such as sodium acetate, asthe reaction solvent, but other methods may be employed, if desired. Thereactants may be added simultaneously or consecutively, as desired, butit is desirable that the 2-haloethylamine hydrohalide not be placed inbasic solution unless that solution already contains theacetonedicarboxylate, to avoid the formation of aziridines. Typically,the 2-haloethylamine hydrohalide and acetonedicarboxylate are dissolved,either simultaneously or in the order stated, in water, and a solid weakbase added to produce the reaction mixture. The reaction is preferablyconducted at a temperature between 0° and 35° C., more preferably atabout room temperature, i.e. between about 15° and 30° C.; over a timepreferably between about 30 minutes and 24 hours, more preferablybetween about 4 and 18 hours. The intermediate di(lower alkyl)3-(2-haloethylamino)-2-pentenedioate ("haloenamine") typicallycrystallizes and may be isolated by filtration, as a mixture of the Eand Z isomers. Each R is preferably methyl, X is preferably bromine orchlorine, and sodium acetate is preferably used to control pH.

In Alternate II, the di(lower alkyl) 1,3-acetonedicarboxylate is treatedwith 2-hydroxyethylamine (2-aminoethanol) in an aprotic polar solvent toproduce the hydroxyenamine (XIV), which is then converted to thehaloenamine (XIII) via the mesylenamine (XV). The conversion may stop atthe mesylenamine stage, and the mesylenamine be cyclized directly (Step2, Alternate II) if desired. Typically, the dicarboxylate is dissolvedin the solvent, the 2-hydroxyethylamine is added slowly to the resultingsolution, and the water formed during the reaction is removed byazeotropic distillation. While the hydroxyenamine may be formed underless stringent conditions (see, e.g., U.S. Pat. No. 4,089,969), ananhydrous solution of the hydroxyenamine is required for the nextreaction, and it is therefore convenient to carry out the formation ofthe hydroxyenamine in an aprotic medium. The resultng solution containsa mixture of the E and Z isomers of the hydroxyenamine, and may be usedwithout purification in the next step. As in Alternate I, a preferred Ris methyl. A preferred solvent is dichloromethane.

Esterification of the hydroxyenamine (XIV) with mesyl chloride in thepresence of an organic base such as a tertiary amine, optionally in thepresence of an aprotic polar solvent, takes place at a temperaturebetween about -10° C. and room temperature, preferably between about 0°and 10° C. Conveniently, the tertiary amine is added to the solutionfrom the previous reaction, which has been cooled to the appropriatetemperature, and the mesyl chloride is added slowly to the resultingsolution over a period between about 30 minutes and 10 hours, typicallyabout 2 to 5 hours. The solution of the resulting mesylenamine (XV) isquenched with water, and solvent removed from the organic phase toafford a mixture of the E and Z isomers of the mesylenamine (XV), whichmay be used without further purification in the next reaction, thoughpurification is preferable if the mesylenamine is to be cyclizeddirectly rather than to be first converted to the haloenamine.

The mesylenamine (XV) is converted into the corresponding haloenamine(XIII) by reaction with an anhydrous alkali halide, preferably a bromideor iodide, e.g. sodium iodide, lithium bromide, etc., in an aproticpolar solvent at a temperature between about room temperature and thereflux temperature of the solvent, e.g. between about 30° and 100° C.,for 1 to 30 hours, e.g. between 5 and 20 hours, the period depending onthe reagents and reaction temperatures. The haloenamine (XIII) may bereadily isolated by adding water to the reaction mixture, washing theorganic phase, and removing the solvent to afford a mixture of the E andZ isomers of the haloenamine, which may conveniently be purified byrecrystallization.

Preparation of Compounds of Formula XII

In Step 2, the haloenamine (XIII) or mesylenamine (XV) from Step 1 iscyclized with a strong base in an aprotic polar solvent.

In Alternate I (which is preferred), typically the haloenamine isdissolved in the solvent, and from 1 to 2 equivalents, preferably from1.1 to 1.5 equivalents, of the strong base added in solid form. If thebase is not soluble in the solvent, it may be desirable to add aphase-transfer catalyst, such as a tetraalkylammonium halide, etc., toenhance the rate of reaction. The reaction occurs preferably betweenabout 15° and 35° C., more preferably at about room temperature, overfrom about 1 to 30 hours. The resulting cyclic enamine (XVI) may beisolated, for example by water extraction of the solution andevaporation of the solvent, and may conveniently be purified bydistillation (e.g. Kugelrohr) and/or recrystallization. The E and Zisomers may be separated, if desired, but it is unnecessary to do so, asthey both react in Step 3. X is preferably Br; and preferred strongbases and solvents are sodium methoxide in dichloromethane, sodiumhydroxide in tetrahydrofuran or dimethylsulfoxide, sodium hydride intetrahydrofuran, etc.

In Alternate II (cyclization of the mesylenamine (XV)), a similarprocess to that described above is performed, but the quantities of baseemployed are generally larger, e.g. up to 6 equivalents based on themesylenamine, and the reaction conditions more stringent (highertemperatures, e.g. up to solvent reflux temperature, and longer times).A preferred base/solvent combination is aqueous sodiumhydroxide/dichloromethane, using a phase transfer catalyst.

In Step 3, the pyrrole ring of the pyrrolo-pyrrole is formed by reactionof the cyclic enamine (XVI) with a 2-haloacetaldehyde, XCH₂ CHO, where Xis as previously defined. The process is preferably conducted in aqueoussolution at a pH between 4.5 and 10, preferably between 5 and 8.5. Thereaction is preferably carried out between 15° and 35° C., morepreferably at about room temperature, for from about 1 to 10 hours,preferably between 2 and 5 hours. X is preferably Br, and pH control ispreferably achieved by the presence of a weak base, e.g. sodium acetateor sodium bicarbonate, in the solution. The process is preferablycarried out in the presence of 10 to 50 volume percent of awater-miscible co-solvent, such as methanol.

Typically, the cyclic enamine (XV) is added to an aqueous solution ofthe 2-haloacetaldehyde and a weak base. A water-miscible co-solvent ispreferably also added. The mixture is stirred for the appropriate time,and the resulting compound of formula XII may be isolated from thereaction mixture, e.g. by evaporation of the solvent, and purified asdesired. The 2-haloacetaldehyde may be obtained commercially or preparedby any desired route. In the case of the preferred 2-bromoacetaldehyde,exemplary preparative methods include the acid hydrolysis of a2-bromoacetaldehyde di(lower alkyl) acetal, a lower alkyl1,2-dibromoethyl ether, 1,2-dibromoethyl acetate, etc., each of whichresults in an aqueous solution of 2-bromoacetaldehyde.

If the dicarboxylic acid (XII, R=H) is desired, (XII) may be saponifiedby conventional chemical means, e.g. reaction with a strong base toremove the ester groups and treatment with acid to generate thedicarboxylic acid. The diester is dissolved in an aqueous alkali metalhydroxide or carbonate solution, e.g., sodium hydroxide solution, whichmay also contain a water-miscible co-solvent, e.g., methanol, at atemperature between about room temperature and the solvent refluxtemperature for from about 30 minutes to 24 hours, e.g. 1 to 4 hours.The cooled solution is then acidified with an aqueous strong acid, e.g.35% hydrochloric acid, and the dicarboxylic acid precipitates and may beremoved by filtration. The dicarboxylic acid may be purified byconventional means, especially conveniently by recrystallization fromaqueous solution.

The C-1 acid group of the resulting dicarboxylic acid (XII, R=H) maythen be selectively esterified, and the 1-ester-7-acid decarboxylated toafford the pyrrolo-pyrrole-1-carboxylate, which may be 5-aroylated toafford compounds of formula I, all by methods described in the patentsset forth in the "Background to the Invention" section of thisapplication, e.g. U.S. Pat. No. 4,089,969.

EXAMPLES

The following Examples illustrate this invention, but are not intendedto limit its scope.

Example 1 Preparation of dimethyl 3-(2-bromoethylamino)-2-pentenedioate(Step 1, Alternate I)

A. 2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved inwater (30 mL) at room temperature (20° C.) with stirring, and dimethyl1,3-acetonedicarboxylate (10.0 g, 57 mmol) was added. After 5-10minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added,and stirring continued. After approximately 80 minutes, precipitation ofdimethyl 3-(2-bromoethylamino)-2-pentenedioate began, and the solutionwas stirred for 17 hours at room temperature. The thick slurry wasdiluted with cold water (20 mL), and aged at 0°-50° C. for 30 minutesand filtered, and the precipitate washed with cold (0°-5° C.) water (50mL) and dried to constant weight, to afford 13.9 g (86% yield) ofdimethyl 3-(2-bromoethylamino)-2-pentenedioate as a white solid, m.p.71°-72° C.

B. Substituting 2-chloroethylamine hydrochloride (7.0 g, 60 mmol) forthe 2-bromoethylamine hydrobromide in the procedure of part A of thisExample, there was obtained 10.8 g (80% yield) of dimethyl3-(2-chloroethylamino)-2-pentenedioate as a white solid, m.p. 75°-76° C.

C. Substituting for dimethyl 1,3-acetonedicarboxylate in the procedureof parts A or B of this Example,

diethyl 1,3-acetonedicarboxylate,

dipropyl 1,3-acetonedicarboxylate,

di(i-propyl) 1,3-acetonedicarboxylate,

di(t-butyl) 1,3-acetonedicarboxylate, or

dihexyl 1,3-acetonedicarboxylate, one obtains, respectively,

diethyl 3-(2-bromoethylamino)-2-pentenedioate,

dipropyl 3-(2-bromoethylamino)-2-pentenedioate,

di(i-propyl) 3-(2-bromoethylamino)-2-pentenedioate,

di(t-butyl) 3-(2-bromoethylamino)-2-pentenedioate,

dihexyl 3-(2-bromoethylamino)-2-pentenedioate,

diethyl 3-(2-chloroethylamino)-2-pentenedioate,

dipropyl 3-(2-chloroethylamino)-2-pentenedioate,

di(i-propyl) 3-(2-chloroethylamino)-2-pentenedioate,

di(t-butyl) 3-(2-chloroethylamino)-2-pentenedioate, or

dihexyl 3-(2-chloroethylamino)-2-pentenedioate.

Example 2 Preparation of dimethyl 3-(2-bromoethylamino)-2-pentenedioate(Step 1, Alternate II)

A. Dimethyl 1,3-acetonedicarboxylate (196.1 g, 1.13 mol) was placed in a3 L three-neck flask containing a stirrer bar and fitted with athermometer, a water extractor on a reflux condenser, and an additionalfunnel; and the flask then purged with nitrogen. The extractor wasfilled with dichloromethane, and dichloromethane (800 mL) added to theflask. Ethanolamine (68.8 g, 1.13 mol) was added via the addition funnelover 10 minutes, and the mixture warmed to 30° C. The mixture was thenheated under reflux for 24 hours, by which time thin-layerchromatography indicated that very little residual dicarboxylateremained and 20 mL water had collected in the extractor.

The solution of dimethyl 3-(2-hydroxyethylamino)-2-pentenedioate wascooled to 0° C., and triethylamine (235 mL, 170.6 g, 1.69 mol) was addedin one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was addeddropwise via an addition funnel over 3.75 hours, with the temperaturerising to 5°-7° C. The medium-yellow slurry darkened to yellow-orange asthe last 10 mL methanesulfonyl chloride was added. The mixture wasstirred at 0° C. for an additional 2 hours, and water (250 mL) added.The organic phase was washed with water (4×500 mL) and brine (250 mL),and dried overnight over anhydrous magnesium sulfate. After filtration,the solvents were evaporated on a rotary evaporator under reducedpressure at 50° C. to afford 310.0 g (93% yield) of dimethyl3-(2-methanesulfonylethylamino)-2-pentenedioate as a red oil. Themesylenamine may be purified at this point, if necessary or desired, andmay be converted to the haloenamine by the following method or useddirectly in Step 2, Alternate II.

Dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate (156.3 g, 529mmol) was added to a 2 L three-neck flask, which was fitted with amechanical stirrer, thermometer, and reflux condenser. Dichloromethane(750 mL) was added and stirred until the mesylate had completelydissolved, anhydrous lithium bromide (69.0 g, 794 mmmol) was added, andthe mixture stirred at 35° C. for 19 hours. The mixture was cooled to 0°C. and water (250 mL) added, then stirred for 5 minutes and the phasesseparated. The organic phase was washed with water (3×250 mL) and brine(150 mL), and dried over anhydrous potassium carbonate for 15 minutes.Rotary evaporation of the solvent under reduced pressure (50° C.) gave128.4 g of crude dimethyl 3-(2-bromoethylamino)-2-pentenedioate as ayellow oil, which quickly solidified to a yellow solid. The crudematerial was purified by extraction into boiling hexane (5×750 mL) andrecrystallization from hexane, and the pot residues extracted andrecrystallized, to give a total of 90.8 g (61.2% yield) of dimethyl3-(2-bromoethylamino)-2-pentenedioate as white needles. An NMR spectrumin CDCl₃ indicated an Z/E isomer ratio of 19:1, and remeasurement of theCDCl₃ solution after three days indicated an Z/E ratio of 4:1. The twoisomers were not separated.

B. In a similar manner to that of part A of this Example, using sodiumiodide in place of lithium bromide, and acetone or acetonitrile in placeof dichloromethane, there was obtained in each instance crude dimethyl3-(2-iodoethylamino)-2-pentenedioate as a light brown oil, which couldbe purified by conventional methods.

C. Substituting lithium chloride for lithium bromide, and using asimilar procedure to that in part A of this Example, one obtainsdimethyl 3-(2-chloroethylamino)-2-pentenedioate.

D. Similarly, using other di(lower alkyl) 1,3-acetonedicarboxylates inthe procedures of parts A through C of this Example, one obtains otherdi(lower alkyl) 3-(2-haloethylamino)-2-pentendioates.

Example 3 Preparation of methyl3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate (Step 2)

A. (Alternate I) Dimethyl 3-(2-bromoethylamino)-2-pentenedioate (5.00 g,17.8 mmol) was added to a 100 mL flask containing a stirrer bar.Dichloromethane (50 mL) was then added, and the mixture stirred untilcomplete dissolution occurred. Sodium methoxide (1.92 g, 35.5 mmol) wasadded in portions over 18 minutes, with some heat evolution. Thereaction mixture was stirred at room temperature for 23 hours, thenextracted with water (4×50 mL) and brine (50 mL) and dried overanhydrous magnesium sulfate. Rotary evaporation of the solvents gave2.27 g of a pale yellow solid, which was separated by preparativethin-layer chromatography into three components. The major product wasrecrystallized from hexane to afford crystalline methyl(Z)-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate, m.p. 84°-85° C.,

NMR (CDCl₃): δ: 7.8-8.0 (1H, broad singlet); 4.70 (1H, doublet, J=0.67Hz); 3.75 (3H, singlet); 3.64 (3H, singlet); 3.5-3.8 (3H, multiplet);2.1-2.5 (2H, multiplet).

A minor product was isolated as an oil, methyl(E)-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate,

NMR (CDCl₃): δ: 7.8-8.0 (1H, broad singlet); 4.64 (1H, singlet); 4.08(1H, doublet, J=11 Hz); 3.77 (3H, singlet); 3.65 (3H, singlet); 3.55(1H, doublet, J=11 Hz); 3.5-3.9 (1H, multiplet); 2.0-2.4 (2H,multiplet).

A very minor product was also isolated as an oil, dimethyl3-(1-aziridinyl)-2-pentendioate.

B. (Alternate I) To a solution of dimethyl3-(2-chloroethylamino)-2-pentenedioate (4.71 g, 20 mmol) indichloromethane (50 mL) was added sodium methoxide (1.62 g, 30 mmol) infour equal portions over 45 minutes at room temperature. The reactionmixture, which had developed some yellow color and precipitate, wasstirred for 27 hours, then worked up as described in part A of thisExample to yield 2.8 g of a yellow oil, which was determined bypreparative thin-layer chromatography and NMR to contain methyl (Z)- and(E)-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylates.

C. (Alternate I) To a solution of dimethyl3-(2-iodoethylamino)-2-pentenedioate (3.3 g, 10 mmol) in tetrahydrofuran(distilled, 20 mL) was added tetrabutylammonium bromide (0.32 g, 1 mmol)and sodium hydroxide beads (0.41 g, 10.3 mmol), and the resultingmixture stirred at room temperature for 5.5 hours, during which itdeveloped a lime color. Dichloromethane (30 mL) and water (20 mL) wereadded, and the mixture stirred for 5 minutes, giving a light brown upperaqueous layer and a pale yellow lower organic layer. The organic layerwas separated, and the aqueous layer washed with dichloromethane (2×20mL). The washings were combined with the organic layer, and the combinedorganic phase washed with water (2×20 mL) and brine (20 mL). Removal ofthe solvents by rotary evaporation gave 1.8 g (90% yield) of a lightbrown oil, which solidified on standing. Thin-layer chromatography andNMR spectra indicated major and minor proportions of methyl (Z)- and(E)-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylates, with a very minorproportion of the elimination product dimethyl3-(vinylamino)-2-pentenedioate.

D. (Alternate I) Similarly, using other di(lower alkyl)3-(2-haloethylamino)-2-pentenedioates and, optionally, other strongbases and/or aprotic polar solvents, in the procedures of parts Athrough C of this Example, one obtains other (lower alkyl) 3-(loweralkoxy)carbonyl-2-pyrrolidinylidenecarboxylates.

E. (Alternate II) To a nitrogen-purged three-neck 1 L flask containing aspin bar and fitted with a reflux condenser were added sodium hydroxide(32.00 g, 800 mmol) and water (32.0 mL), and these were stirred untilcomplete solution was obtained. Dichloromethane (640 mL) was then added,followed by dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate(40.12 g, 136 mmol) and tetrabutylammonium bromide (6.57 g, 20 mmol).The reaction mixture was heated at reflux for 7 hours, at which timethin-layer chromatography revealed the presence of a small quantity ofstarting mesylenamine. The reaction mixture was therefore stirred for afurther 14 hours at room temperature, at which time thin-layerchromatography showed no mesylenamine remaining, then washed with water(3×200 mL) and brine (200 mL), and dried over anhydrous magnesiumsulfate to afford a yellow solution. Rotary evaporation of the solventunder reduced pressure gave a red, mobile liquid, which was distilled(Kugelrohr, 0.3 mm Hg, 50°-55° C.) to afford 19.74 g (72.9% yield,distilled) of a mixture of methyl (Z)- and(E)-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylates as a clear,colorless oil.

F. (Alternate II) Similarly, using other di(lower alkyl)3-(2-mesylethylamino)-2-pentenedioates and, optionally, other strongbases and/or aprotic polar solvents, in the procedure of part E of thisExample, one obtains other (lower alkyl) 3-(loweralkoxy)carbonyl-2-pyrrolidinylidenecarboxylates.

Example 4 Preparation of dimethyl2,3-dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylate (Step 3)

A. 2-Bromoacetaldehyde dimethyl acetal (1.70 g, 10 mmol), hydrobromicacid (48.5%, 0.25 mL, 2 mmol), and water (2.5 mL) were heated at refluxfor 75 minutes, to provide a solution of 2-bromoacetaldehyde. Thesolution was cooled to room temperature, and sodium acetate (0.50 g)added. The resulting solution was added over 3 hours to a stirredmixture of methyl 3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate (1.00g, 5 mmol), sodium acetate (3.10 g), and water (2 mL) in methanol (10mL). The mixture was stirred an additional hour, and most of thesolvents then removed by vacuum evaporation. The residue was dissolvedin dichloromethane (100 mL), and the solution washed with aqueous sodiumbicarbonate (2×25 mL) and dried over anhydrous magnesium sulfate.Removal of the solvent by evaporation gave 1.26 g of dimethyl2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate.

B. Substituting 2-chloroacetaldehyde diethyl acetal for2-bromoacetaldehyde diethyl acetal, and using a similar procedure tothat in part A of this Example, one obtains dimethyl2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate.

C. Similarly, substituting other (lower alkyl) 3-(loweralkoxy)carbonyl-2-pyrrolidinylidenecarboxylates, such as ethyl3ethoxycarbonyl-2-pyrrolidinylidenecarboxylate, n-propyl3-propoxycarbonyl-2-pyrrolidinylidenecarboxylate, etc., for theequivalent materials in parts A and B of this Example, one obtains otherdi(lower alkyl)2,3-dihydro-1H-pyrrolo[1,2-a]-pyrrole-1,7-dicarboxylates, such asdiethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate,di(n-propyl) 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate,etc.

Example 5 Preparation of2,3-dihydro-1H-pyrrolo[1,2-a]-pyrrole-1,7-dicarboxylic acid

A. Dimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (1.26g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) were heated in water(10 mL) at reflux for 1 hour. The resulting solution was cooled to 0° C.and acidified with hydrochloric acid (12M) to pH 1.2,3-Dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid (0.70 g,71.4% yield) was collected by filtration and dried.

B. Similarly, substituting for the dimethyl2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate of part A of thisExample, diethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate,and similar di(lower alkyl)2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates, one obtains2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid.

We claim:
 1. A process for producing a compound of formula XII, ##STR9##in which each R is independently lower alkyl,which comprises thereaction of a compound of formula XVI, ##STR10## in which R is asdefined above, with a 2-haloacetaldehyde, XCH₂ CHO, in which X ishalogen,in aqueous solution.
 2. The process of claim 1 wherein thereaction temperature is between about 15° and 35° C.
 3. The process ofclaim 2 wherein the reaction temperature is about room temperature. 4.The process of claim 1 wherein the reaction pH is between about 4.5 and10.
 5. The process of claim 4 wherein the reaction pH is between about 5and 8.5.
 6. The process of claim 1 wherein the aqueous solution is anaqueous solution of a weak base.
 7. The process of claim 6 wherein theweak base is selected from sodium acetate and sodium bicarbonate.
 8. Theprocess of claim 1 wherein the aqueous solution contains awater-miscible co-solvent.
 9. The process of claim 8 wherein theco-solvent is from 10 to 50 volume percent of methanol.
 10. The processof claim 1 wherein each R is CH₃ and X is Br or Cl.
 11. The process ofclaim 10 wherein X is Br and the 2-bromoacetaldehyde is prepared by acidhydrolysis of its di(lower alkyl)acetal.